Pain is experienced in the body via nerve signaling (e.g., from a noxious stimulus to a peripheral nerve), which transmits an impulse via the nerve axon and neurochemical transmission to other nerves in a path up the spinal cord to the brain. There are a wide variety of potential noxious stimuli, including noxious alterations in pressure, temperature, nerve damage from external sources or internal disease and degeneration, inflammatory molecules, and so forth. For many conditions, exact diagnosis and treatment will lead to resolution of pain, or at least amelioration thereof. However, in many instances, the cause may not be ascertainable, and/or available treatment options may be ineffective or unacceptably harmful. Patients and physicians are then left to try analgesics. In these applications, such medicines are nonspecific, may be inadequate in effect, may be harmful, or have unwanted side effects.
Two major types of nervous system pathology include (1) disturbances of neurotransmitter function/modulation (hereinafter "neurotransmitter dysregulation syndromes"), and (2) diseases of the nerves themselves (hereinafter "neuropathies"). A representative neurotransmitter dysregulation syndrome includes fibromyalgia (FM), and representative neuropathies include diabetic and alcoholic neuropathies, as well as complications resulting from use of certain indications and aging. FM is a common condition characterized by a history of chronic generalized pain and physical exam evidence of at least 11 of 18 defined "tender point" sites in muscles and connective tissue (Wolfe et al., Arthritis Rheum 33:160-72, 1990). Commonly associated conditions include irritable bowel syndrome, headache, irritable bladder syndrome (interstitial cystitis), sleep disturbance, and fatigue (Goldenberg, Current Opinion in Rheumatology 8:113-123, 1996; Moldofsky et al., Psychosom Med 37:341-51, 1975; Wolfe et al., 1990; Wolfe et al., J Rheum 23:3, 1996; Yunus et al., Semin Arthritis Rheum 11:151-71, 1981). The prevalence in the general population is approximately 2% and occurs predominantly in females (Goldenberg, 1996; Wolfe, Arthitis Rheum 38:19-28, 1995; Wolfe et al., 1996).
A predominant theory regarding the etiology of FM holds that an imbalance and/or dysregulation of neurotransmitter function may occur within the central nervous system (CNS), either in the brain or spinal cord and in the relation of the CNS to muscle and connective tissue via regulatory nerve pathways (Goldenberg, 1996; Russell, Rheum Dis Clin NA 15:149-167, 1989; Russell et al., J Rheumatol 19:104-9, 1992; Vaeroy et al., Pain 32:21-6, 1988; Wolfe et al., 1996). Neurotransmitters are chemical messengers, neuropeptides, emitted from nerve cells that interact with receptors on other nerve cells, as well as other cell types, including muscle and immune cells. Neurotransmitter imbalance, which leads to increased pain experience, may include a qualitative and/or quantitative decrease in the function of such neurotransmitters as serotonin, norepinephrine, dopamine, endorphins, and encephalins and an increase in the irritative neurotransmitter, substance P. This imbalance results in amplified modulation of pain-signaling in the central nervous system, resulting in neurogenic pain (Matucci-Cerinic, Rheumatic Disease Clinics of North America 19:975-991, 1993; Bonica, The Management of pain, Lea and Febiger, 2d ed., Philadelphia, pp. 95-121, 1990). Similar mechanisms may be at work to cause associated conditions; for example, dysregulation of neurotransmitter signaling in the bowel musculature, leading to irritable bowel syndrome symptoms such as cramping, diarrhea, and/or constipation.
At the current time, treatment options for FM are generally not optimally effective. Low doses of antidepressant medications may improve neurotransmitter dysregulation, leading to partial and temporary improvement in pain (Goldenberg et al., Arthritis Rheum 29:1371-7, 1986; Simms, Ballieres Clin Rheumatol 8:917-934, 1994; Wolfe et al., 1996). Analgesics, muscle relaxants, and nonsteroidal anti-inflammatory drugs may have a mild beneficial effect on pain (Simms; Wolfe et al., 1996). Physical modalities such as physical therapy, stretching, and exercise can partially help, as can acupuncture (Burckhardt et al., Scan J Rheumatol 94:51, 1992; Simms; Wolfe et al., 1996). Stress reduction techniques and psychological counseling may allow the patient to accommodate to the symptoms (Burckhardt et al.; Simms; Wolfe et al., 1996). FM is usually a chronic condition and can be as disabling as rheumatoid arthritis (Griep; Hawley et al., J Rheumatol 18:1552-7, 1991; Martinez et al., J Rheumatol 22:270-274, 1995; Mason et al., Arthritis Rheum (suppl) 32:5197, 1989; Wolfe et al., J Rheum 23:3, 1996). Clearly, additional and more effective treatments are needed to reduce suffering from this condition.
Whereas FM exemplifies a neurotransmitter dysregulation syndrome, there are numerous conditions characterized by ultrastructural change of the nerves themselves, as mentioned above, called neuropathies (Adams, Principles of Neurology, Victor M. (eds.), 4th ed., 1989, McGraw Hill, New York; Bonica).
Diseases of the sensory nerves, as well as sympathetic and parasympathetic nerves of the peripheral nervous system, can yield pain and other unpleasant sensations called paresthesia or dysesthesia. These can be classified according to where pathology occurs, e.g., the anterior or lateral horns of the spinal cord, the dorsal root or sympathetic ganglia, as well as whether the nerve (axon) itself or myelin sheath is affected. Pathologic processes can include aging, infection, ischemia, immunologic inflammation, direct toxic effects, and other insults. Examples of painful neuropathies, especially effecting the extremities, include those associated with diabetes, alcoholism, shingles, side effects of various medications, cancers, autoimmune diseases, sympathetic dystrophies, and aging. In many cases, no specific etiology is found. These conditions are unfortunately common and treatment approaches are only minimally helpful. Examples of treatments include analgesic, anti-depressant, and anti seizure medications. Unfortunately, these tend to be only partially helpful and may have harmful side effects.
Accordingly, there is a need in the art for compositions and methods for treating pain generally associated with disturbances of the nervous system, including diseases of the central and peripheral nervous system, as well as pain induced by neuropeptide dysfunction. Such methods should also avoid the disadvantages typically associated with oral or systemic delivery of pain medications. The present invention fulfills these needs and provides other related advantages.